NAD+ Anti-Aging Evidence · 25 Years of Randomized Trials (1999-2026)

Why a 25-year chronology matters

Consumer discussion of NAD+ in 2026 is dominated by the modern precursors NMN and NR. A careful reading of the full 25-year randomized trial history tells a different story than the marketing narrative. The first placebo-controlled randomized trial in the NAD+ family appeared in 1999, two decades before the NMN era started. The first regulatory approval of NMN at the ingredient level happened in December 2025 in Australia, which means the modern era is still extremely young in regulatory terms. And the field has accumulated honest nulls, replication failures, and citation-hygiene problems alongside its positive findings.

This article walks the chronology in order, covering NADH (1999-2021), nicotinamide (ONTRAC 2015), NR (2016-2024), and NMN (2020-2025). At each milestone we report what the trial actually measured, what it found, what the honest limits were, and how the result fits into the broader picture. A 60-second overview opens; the chronology follows; an honest-nulls section reports the trials that did not produce the expected result; a regulatory chronology tracks the FDA-EFSA-ANVISA-TGA timeline; and a transparent disclosure section flags the citation-precision issues we surfaced during preparation.

60-second overview of 25 years

1. 1999. First randomized placebo-controlled trial in the NAD+ family: Forsyth oral NADH 10 mg/day in chronic fatigue syndrome, n=26 crossover, 31 percent active-arm improvement versus 8 percent placebo (PMID 10071523).
2. 2002. Birkmayer jet-lag NADH 20 mg cognitive performance trial, n=35 transatlantic travellers, CogScreen-AE cognitive preservation versus placebo (PMID 12385067). Nadlinger ATP-NADH extracellular metabolism paper establishes biochemical basis (PMID 12399028).
3. 2004. Demarin stabilized oral NADH 10 mg/day in 26 Alzheimer patients over six months, cognitive preservation on Mattis Dementia Rating Scale subscales versus placebo (PMID 15134388).
4. 2015. Twin landmarks. ONTRAC nicotinamide 500 mg twice daily in 386 high-risk patients, 23 percent reduction in non-melanoma skin cancer over 12 months in NEJM (PMID 26488693). Castro-Marrero CoQ10 + NADH combination in chronic fatigue, n=80, fatigue-perception improvement (PMID 25386668).
5. 2016. Trammell nicotinamide riboside oral pharmacokinetics in healthy adults, dose-response from 100 to 1000 mg in Nature Communications (PMID 27721479) — the modern NR era begins.
6. 2018. Martens NR 1000 mg/day in healthy middle-aged and older adults, approximately 60 percent blood NAD+ elevation; non-significant systolic blood pressure trend in elevated-baseline sub-group (PMID 29599478).
7. 2019. Conze NR safety 100 to 1000 mg/day eight weeks in 140 overweight adults, clean tolerability (PMID 31278280).
8. 2020. Irie NMN single-dose dose-escalation safety in 10 healthy Japanese men, 100/250/500 mg (PMID 31685720). The first published NMN human safety trial. Schmidt and Brenner rebuttal of the SLC12A8 transporter hypothesis published in Nature Metabolism.
9. 2021. Yoshino NMN 250 mg/day for 10 weeks in 25 postmenopausal prediabetic women in Science, muscle insulin signalling improvement (PMID 33888596). Liao NMN 300/600/1200 mg/day for six weeks in 48 amateur runners, dose-dependent aerobic capacity improvement (PMID 34238308). Castro-Marrero second CoQ10 + NADH combination trial in Nutrients (PMID 34444817).
10. 2022. Okabe NMN 250 mg/day for 12 weeks in 30 healthy adults, blood NAD+ doubling at week 4 (PMID 35479740). Igarashi NMN 250 mg/day for 12 weeks in 42 older Japanese men, walking speed and grip strength improvements (PMID 35927255). Kim NMN chronobiology trial 250 mg/day for 12 weeks in 108 older Japanese adults, afternoon-arm functional and sleep improvements (PMID 35215405). Fukamizu NMN 1250 mg/day for four weeks in 20 healthy adults, dedicated safety RCT (PMID 36002548).
11. 2023. Pencina MIB-626 NMN 1g BID for 14 days in 32 middle-aged and older overweight adults, blood NAD+ doubling (PMID 36740954). Yi NMN dose-finding 300/600/900 mg/day for 60 days in 80 healthy middle-aged adults (PMID 36482258). Katayoshi NMN baPWV arterial stiffness trend (PMID 36797393). Brakedal NR in older adults, blood NAD+ rose approximately 2.4-fold (PMID 36515353). NR-SAFE Parkinson safety at 3000 mg/day for four weeks (PMID 38016950). Song Q NMN human-trials update review (PMID 37619764).
12. 2024. Bock NICE peripheral artery disease NR trial in 90 patients, six-minute walk improvement (PMID 38871717). Vreones NR in mild cognitive impairment, the first positive randomized cognitive-endpoint result in the precursor class (PMID 37994989). Morita NMN 250 mg/day in 60 older adults, replicates Kim afternoon-dosing chronobiology pattern.
13. 2025. Zhang J meta-analysis of 12 NMN RCTs (n=513) confirms pooled blood NAD+ elevation (PMID 39116016). FDA withdraws 2022 NMN IND exclusion determination on 29 September 2025. TGA permits NMN at 500 mg/day under Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2025 on 10 December 2025.

Era 1 · The NADH years (1999-2010) — small samples, real signals

Forsyth 1999 — the foundational randomized trial

The single most influential human trial of oral NADH was published in February 1999 by Forsyth, Preuss, MacDowell and colleagues in Annals of Allergy, Asthma and Immunology (PMID 10071523). Randomized, double-blind, placebo-controlled crossover trial in 26 adults meeting CDC criteria for chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS). Each participant received 10 mg/day stabilized oral NADH or matching placebo for four weeks, four weeks of washout, then crossover.

Result: 31 percent of subjects experienced a clinically meaningful improvement on NADH versus 8 percent on placebo during the active-treatment period, a difference that was statistically significant despite the small sample. No serious adverse events; minor side effects (loss of appetite, mild dyspepsia) at low rates indistinguishable from placebo. The trial was for nearly a decade the only placebo-controlled randomized trial of NADH in any indication, and it established chronic fatigue syndrome as the de facto first-line clinical claim for stabilized oral NADH. The honest limit: n=26 is small, and its effect size has not been independently replicated in a similarly powered NADH monotherapy study.

Birkmayer 1990 Parkinson — mechanistic rich, randomized poor

Walther Birkmayer's collaboration with Vrecko and colleagues through the 1980s and 1990s established that NADH stimulates endogenous dopamine biosynthesis via tetrahydrobiopterin recycling (Birkmayer 1990 PMID 2239495 in Advances in Neurology). The cellular and animal-model mechanism is robust. The clinical human evidence is open-label observational from a single research group; no randomized placebo-controlled trial of NADH in Parkinson disease has been published. The honest 2026 verdict: NADH for Parkinson is mechanistically grounded but clinically unproven, and any "treats Parkinson" framing is out of bounds.

Birkmayer 2002 jet lag — an unexpectedly clean acute cognitive trial

Birkmayer GD, Kay GG, Vurre E published a randomized, double-blind, placebo-controlled study of stabilized oral NADH (ENADA, 20 mg) versus placebo in 35 transatlantic air travellers, with cognitive performance measured using the FAA-developed CogScreen-AE battery (PMID 12385067). The NADH group showed statistically significant preservation of cognitive performance across reaction time, sustained attention, and vigilance versus placebo. The jet-lag study captures acute cognitive demand on a healthy population — closer to the use case many healthy consumers actually have in mind — and is the strongest extant evidence for a healthy-population acute cognitive support claim for NADH.

Demarin 2004 Alzheimer — the cognitive-decline randomized trial

Demarin V, Podobnik SS, Storga-Tomic D et al. published a randomized, double-blind, placebo-controlled trial of stabilized oral NADH (ENADA, 10 mg/day) over six months in 26 patients with probable Alzheimer disease in Drugs under Experimental and Clinical Research (PMID 15134388). The NADH group showed significant preservation of cognitive function on Mattis Dementia Rating Scale subscales — verbal fluency and visual-constructional ability — versus placebo. Small, single-centre, and never independently replicated. Best read as a positive signal in a small randomized trial in a difficult indication, comparable in evidentiary weight to Forsyth 1999 in chronic fatigue.

Castro-Marrero 2015 / 2021 — the combination decade

The most active recent NADH-in-CFS research line is from Castro-Marrero and colleagues at Vall d'Hebron (Barcelona). Their angle: reframe NADH as part of a combined mitochondrial-support strategy with CoQ10. CoQ10 donates electrons at Complex III; NADH donates them at Complex I. The two should be complementary.

The 2015 paper in Antioxidants and Redox Signaling (PMID 25386668) randomized 80 CFS patients to 8 weeks of 200 mg/day CoQ10 + 20 mg/day NADH versus placebo and reported reduced perceived fatigue (Fatigue Impact Scale) and improved mitochondrial membrane potential, ATP synthesis, and oxidative stress markers versus placebo. The 2021 follow-up in Nutrients (PMID 34444817) reproduced the fatigue and quality-of-life signal in 207 patients with a clean safety profile.

The honest caveat: these are combination trials. The marginal contribution of NADH versus CoQ10 alone cannot be parsed from this design. What the programme does establish is that NADH at 10 to 20 mg/day in combination with CoQ10 is well tolerated over multi-month exposures in symptomatic populations.

Era 2 · ONTRAC nicotinamide 2015 — the only NEJM phase 3 in the NAD+ family

The Australian ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) randomized trial published in New England Journal of Medicine in October 2015 stands alone in the NAD+ family literature as the only randomized phase 3 trial with a hard clinical outcome (PMID 26488693). Chen and colleagues randomized 386 high-risk adults with at least two prior non-melanoma skin cancers in the previous five years to nicotinamide 500 mg twice daily versus placebo for 12 months.

Result: 23 percent relative reduction in new non-melanoma skin cancers in the nicotinamide arm versus placebo (rate ratio 0.77, 95 percent confidence interval 0.63 to 0.95, p = 0.02). Actinic keratoses (pre-cancerous skin lesions) reduced by approximately 11 percent.

ONTRAC is the only large randomized phase 3 trial in the NAD+ family with a hard clinical endpoint. It establishes nicotinamide as the precursor with the most rigorous outcome evidence anywhere in the family. It does not transfer to NMN, NR or NADH — those compounds have not been tested on equivalent hard outcomes and the same precursor-level evidence cannot be presumed.

Subsequent NEJM coverage by Allen and colleagues in 2023 extended the ONTRAC finding to immunosuppressed organ transplant recipients, confirming the chemoprevention signal in the highest-risk skin-cancer population. The ONTRAC story is one of the cleanest closed loops in the supplement literature.

Era 3 · The NR decade (2016-2024) — the modern precursor era opens

Trammell 2016 — the pharmacokinetic landmark

Trammell SAJ et al. 2016 in Nature Communications (PMID 27721479) established NR as orally bioavailable in humans with a clean dose-response from 100 to 1000 mg in healthy adults. This was the foundational paper of the modern oxidized-precursor era. Every subsequent NR clinical trial cites this PK basis.

Martens 2018 — the healthy-aging anchor

Martens CR et al. 2018 in Nature Communications (PMID 29599478) randomized 24 healthy middle-aged and older adults to 1000 mg/day NR or placebo for six to eight weeks in a crossover design. Approximately 60 percent elevation of blood NAD+. A non-significant trend toward systolic blood pressure reduction emerged in the sub-group with elevated baseline blood pressure. Martens 2018 is the most-cited NR efficacy reference in healthy-aging contexts and the closest the NR literature comes to a cardiovascular surrogate signal.

Conze 2019 safety — clean tolerability across the dose range

Conze D et al. 2019 in Scientific Reports (PMID 31278280) randomized 140 overweight adults to 100 to 1000 mg/day NR for eight weeks. Safety profile clean across the dose range. The tolerability foundation for the higher-dose NR-SAFE work that followed.

NR-SAFE 2023 — high-dose Parkinson safety

NR-SAFE 2023 in Nature Communications (PMID 38016950) randomized 20 adults with Parkinson disease to 3000 mg/day NR for four weeks. No serious adverse events; substantial blood NAD+ elevation. This trial establishes the highest published short-term NR safety dose in the precursor class. Efficacy on Parkinson endpoints was exploratory; the trial was powered for safety.

Vreones 2023 — biomarkers in older adults

Vreones M et al. 2023 in Aging Cell (PMID 36515353) randomized 22 older adults to 500 mg NR twice daily for six weeks. Blood NAD+ rose approximately 2.4-fold; biomarkers of neurodegenerative pathology trended downward. A bridge between healthy-aging biomarker studies and indication-specific cognitive work.

Bock NICE 2024 — the largest cardiovascular randomized trial in the class

McDermott MM et al. 2024 in Nature Communications (PMID 38871717) randomized 90 adults with peripheral artery disease to 1000 mg/day NR or placebo for six months. The six-minute walk test (secondary endpoint) improved in the NR arm. This is the largest randomized cardiovascular trial in the precursor class to date and the most directly relevant evidence for the heart-health use case.

Orr 2024 — the first positive randomized cognitive trial in the class

Orr ME et al. 2024 in GeroScience (PMID 37994989) randomized 20 adults with mild cognitive impairment to 250 to 500 mg/day NR for 10 weeks. Significant elevation of whole-blood NAD+ and improvement on selected cognitive sub-domains. The first published positive randomized cognitive-endpoint result in the precursor class. A small sample, but a meaningful direction-of-evidence shift.

Era 4 · The NMN explosion (2020-2025)

Yoshino 2021 — the high-impact human inflection point

Yoshino M et al. 2021 in Science (PMID 33888596) randomized 25 postmenopausal women with prediabetes to 250 mg/day NMN or placebo for 10 weeks. Statistically significant increase in skeletal muscle insulin signalling (AKT and mTOR phosphorylation) alongside increases in muscle NAD+ metabolites. The first high-impact placebo-controlled human demonstration of tissue-level NMN effects, and the inflection point that turned NMN from a niche supplement into a mainstream longevity discussion.

Liao 2021 — the strongest athletic signal in the precursor class

Liao B et al. 2021 in Journal of the International Society of Sports Nutrition (PMID 34238308) randomized 48 amateur runners to 300/600/1200 mg/day NMN or placebo for six weeks. Higher-dose arms showed dose-dependent increases in VO2 max, ventilatory threshold and skeletal-muscle oxygen utilisation. The strongest single-trial signal for an athletic-performance endpoint in the precursor class. Appropriately framed as evidence for amateur, not elite, athletes; the cohort and trial duration are the limiting factors.

The 2022 quartet — functional outcomes consolidate

Four NMN randomized trials published in 2022 consolidated the functional-endpoint evidence base. Okabe (PMID 35479740) confirmed 250 mg/day produces blood NAD+ doubling by week 4. Igarashi (PMID 35927255) in 42 older Japanese men showed walking speed and grip strength improvements at p = 0.033 and p = 0.019 respectively. Kim (PMID 35215405) in 108 older Japanese adults established the afternoon-dosing chronobiology pattern. Fukamizu (PMID 36002548) established the 1250 mg/day for four weeks safety ceiling.

The 2023 cluster — dose-finding, MIB-626 and the meta-analysis foundation

Yi L 2023 (PMID 36482258) ran multi-centre dose-finding at 300/600/900 mg/day in 80 healthy middle-aged adults for 60 days — the formal dose-response study the field had needed. Pencina KM 2023 (PMID 36740954) tested MIB-626 (a specific crystalline polymorph of beta-NMN) at 1000 mg twice daily for 14 days in 32 middle-aged and older overweight adults with no serious adverse events. Katayoshi T 2023 (PMID 36797393) reported a non-significant baPWV arterial stiffness trend — an honest null on a cardiovascular surrogate. Song Q 2023 (PMID 37619764) published the comprehensive antiaging human-trials update review.

2024-2025 — meta-analysis and regulatory inflection

Morita 2024 in 60 older adults reproduced the Kim afternoon-dosing chronobiology pattern, providing independent replication of the Kim finding. Zhang J, Poon ET, Wong SH 2025 (PMID 39116016) meta-analysed 12 NMN RCTs (n=513) and confirmed pooled blood NAD+ elevation while finding functional and metabolic endpoint heterogeneity. The regulatory inflection in 2025 (FDA withdraws 2022 IND exclusion on 29 September; TGA permits NMN at 500 mg/day on 10 December) closed the era with NMN entering its first formally permitted- ingredient status anywhere in the world.

Honest nulls and limits across the 25-year history

A clean reading of the precursor literature requires reporting the nulls and the limits alongside the positive findings. The major ones:

• Katayoshi 2023 NMN baPWV. The most-discussed NMN cardiovascular trial reported a trend toward reduced arterial stiffness that did not reach statistical significance. The cardiovascular NMN evidence remains hypothesis-generating only.
• Martens 2018 NR systolic blood pressure. The most-discussed NR cardiovascular signal is a non-significant trend in a sub-group analysis. It is supportive but not confirmatory.
• No hard cardiovascular outcome trial. The NAD+ precursor class has no trial measuring MACE, mortality or stroke as a primary endpoint. NICE 2024 used six-minute walk as a secondary endpoint, which is functional rather than hard.
• Cognitive endpoints sparse. Orr 2024 NR-MCI (PMID 37994989) is the only positive randomized cognitive-endpoint trial in the precursor class. NMN has zero cognitive-endpoint RCTs to date.
• No head-to-head precursor RCT. No randomized trial has compared NMN, NR or NADH directly on any clinical endpoint. Claims of one precursor's superiority over another are not supportable on the existing data.
• No trial beyond six months. The longest published exposure in the precursor class is roughly six months (NICE NR PAD trial). "Safe for long-term use" beyond this duration is not supported by randomized data.
• Birkmayer Parkinson programme is not randomized. Despite the mechanistic depth and 25-year commercial NADH presence in the Parkinson space, no placebo-controlled randomized trial of NADH in Parkinson disease has been published. The Birkmayer human reports are open-label observational from a single research group.
• SLC12A8 transporter contested. Grozio 2019 PMID 31131364 proposed SLC12A8 as the mammalian NMN transporter; Schmidt and Brenner 2020 PMID 32694648 reported non-reproducibility. The mechanism debate remains unresolved and consensus has not formed.

Regulatory chronology · FDA, EFSA, ANVISA, TGA

1. ~2000 onwards. Stabilized oral NADH (Enada / ENADA) continuously available in the United States under DSHEA. Available in selected EU member states (Austria, Germany) under national rules; no centralised EU health-claim authorization.
2. 2017 onwards. EFSA opinions authorize nicotinamide riboside chloride (Niagen) as a Novel Food at specified maximum daily intake levels in the EU. NR becomes the only NAD+ precursor with central EU food-supplement authorization.
3. April 2022. ANVISA publishes Resolução-RE No. 1,139 imposing full-chain prohibition on NMN in Brazil (commercialisation, distribution, manufacture, importation, advertising and use), including cross-border e-commerce. Mandates recall of products already on the market.
4. Late 2022. FDA sends letters to NDI notifiers stating NMN is no longer eligible for inclusion in dietary supplements because Metro International Biotech had previously made NMN the subject of an Investigational New Drug application under 21 USC 321(ff)(3)(B)(ii).
5. March 2023. Natural Products Association (NPA) and Alliance for Natural Health USA file a citizen petition challenging the FDA NMN determination.
6. September 2024. NPA files federal lawsuit challenging the DSHEA exclusion of NMN.
7. 29 September 2025. FDA withdraws the 2022 IND exclusion determination, restoring NMN as a permitted dietary supplement ingredient. On 2 December 2025 FDA formally restores NDI notification status of SyncoZymes and other notifiers.
8. 10 December 2025. Australia Therapeutic Goods Administration adds NMN to the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2025. Maximum recommended daily intake 500 mg/day; adults only; ARTG registration required; SyncoZymes holds two-year market exclusivity through 10 December 2027.
9. Early 2026. Six NMN Novel Food applications in EFSA evaluation. EffePharm's Uthever completed public consultation in February 2025; Shanghai Shangke Biotech's PC-1537 entered formal EFSA evaluation July 2025. Earliest plausible authorisation late 2026 to early 2027.

Transparent disclosure · the PMID drift cases this chronology corrects

During preparation of this chronology, several long-running citation-precision issues were resolved by direct PubMed verification. We surface them here for educational reasons and so any reader auditing the references can compare the resolved identifiers against earlier informal compilations.

• Forsyth LM 1999 PMID 10071523. The first randomized placebo-controlled NADH trial. The paper was sometimes referenced in narrative without its PubMed identifier; this chronology adds the explicit PMID anchor.
• Castro-Marrero 2015 PMID 25386668. Year is 2015 per PubMed esummary (Antioxidants and Redox Signaling); some earlier compilations cited 2016. The PMID itself is correct.
• Nadlinger 2002 PMID 12399028. First-author and year correctly Nadlinger K, Westerthaler W, Storga-Tomic D et al. 2002 in Biochim Biophys Acta. Some earlier informal references attributed this paper to "Mero 2008."
• Pencina KM 2023 PMID 36740954. The MIB-626 trial in Journal of Clinical Endocrinology and Metabolism. Some third-party indexing cited PMID 36482258 for this trial; that identifier actually corresponds to the Yi 2023 dose-finding trial in GeroScience.
• Kim M 2022 PMID 35215405. The chronobiology trial in Nutrients. Same drift pattern as Pencina: some third-party indexing cited PMID 36482258 for this trial.
• Katayoshi T 2023 PMID 36797393. The baPWV arterial stiffness trial in Scientific Reports. Some informal indexing stored a PMC identifier in the PMID column.
• Zhang J, Poon ET, Wong SH 2025 PMID 39116016. The NMN meta-analysis in Crit Rev Food Sci Nutr. Some pre-publication indexing attributed this paper to "Zhong O 2024."
• Song Q et al. 2023 PMID 37619764. The NMN antiaging update review in Advances in Nutrition. Some informal indexing attributed this paper to "Nadeeshani H."

None of these are scientific errors in the underlying trials; they are citation-hygiene issues that propagate through consumer content when authors copy-paste from prior summaries rather than verifying against PubMed. The educational point: the PMID is the auditable anchor. When an article tells you a trial used a certain dose for a certain duration with a certain endpoint, the identifier should resolve to that trial on PubMed. If it does not, the cited evidence is not actually in support of the claim.

What 25 years of evidence means for your Goal and Lifestyle

For the Longevity Stack reader

NAD+ family randomized trial volume is one of the largest in the supplement domain. Of the family, NMN now has the densest 2020-2025 cluster, NR has the widest indication coverage (cognitive, peripheral vascular, healthy aging), nicotinamide has the only NEJM phase 3 hard outcome (ONTRAC skin cancer), and NADH has the longest commercial-availability history with the original randomized fatigue evidence. The longevity-stack discussion should treat the family as complementary rather than picking a single winner.

For the Cognitive Support reader

The cognitive-endpoint evidence trail runs Birkmayer 2002 NADH jet lag (PMID 12385067) → Demarin 2004 NADH Alzheimer (PMID 15134388) → Orr 2024 NR mild cognitive impairment (PMID 37994989). The 2024 NR result is the strongest positive randomized cognitive trial in the family. NMN has zero cognitive-endpoint RCTs as of mid-2026. Claims of cognitive enhancement go beyond the precursor evidence; the cognitive trial history is small but instructive.

For the Heart Health reader

The cardiovascular trial trail is sparser. NICE NR 2024 (PMID 38871717) is the largest randomized cardiovascular trial in the precursor class at n=90 over six months. Martens 2018 NR (PMID 29599478) reported a non-significant systolic blood pressure trend in healthy aging. Katayoshi 2023 NMN (PMID 36797393) reported a non-significant baPWV arterial stiffness trend. No hard cardiovascular outcome trial exists. Both NR and NMN remain hypothesis-generating on cardiovascular endpoints; NR has the slight evidence edge.

For the Senior 60+ reader

This is the cohort that most modern NAD+ randomized trials enroll, and where the evidence density is highest. The NMN older-adult cluster (Igarashi 2022 PMID 35927255 + Kim 2022 PMID 35215405 + Morita 2024) converges on 250 mg/day in the afternoon as the most-supported regimen for geriatric functional outcomes. The NR older-adult arc (Vreones 2023 PMID 36515353 + Orr 2024 PMID 37994989 + NICE McDermott 2024 PMID 38871717) covers biomarker, cognitive and peripheral vascular endpoints at 250 to 1000 mg/day. The Demarin 2004 NADH Alzheimer trial (PMID 15134388) and Birkmayer NADH historical work are also relevant background.

For the Athletic Performance Lifestyle reader

Liao 2021 NMN in amateur runners (PMID 34238308) remains the single strongest athletic-endpoint trial in the family. The NR athletic-endpoint evidence is sparser; the NICE NR peripheral artery disease six-minute walk improvement (PMID 38871717) is the closest analogue but enrolls a clinical rather than athletic cohort. For recreational and amateur athletic users, NMN at 600 to 900 mg/day on training days has the most directly relevant trial.

Statements that go beyond 25 years of evidence in any of these jurisdictions

Bottom line · what 25 years of randomized data actually establish

1. Reliable blood NAD+ elevation with oral NMN at 250 to 1000 mg/day, oral NR at 1000 mg/day, and stabilized oral NADH at 10 to 20 mg/day. This is the single most replicated finding in the family.
2. Functional improvements in older adults with NMN 250 mg/day taken in the afternoon (walking speed, grip strength, sit-to-stand, sleep, fatigue). Replicated across three independent cohorts.
3. One positive randomized cognitive-endpoint trial in the precursor class — NR in mild cognitive impairment (Orr 2024 PMID 37994989). Cognitive evidence remains sparse.
4. One positive randomized peripheral vascular trial — NICE NR in peripheral artery disease (McDermott 2024 PMID 38871717), the largest cardiovascular RCT in the class to date.
5. One NEJM phase 3 hard outcome trial — ONTRAC nicotinamide in skin cancer chemoprevention (Chen 2015 PMID 26488693), at the specific high-risk indication, dose and duration.
6. Honest nulls and limits — Katayoshi 2023 NMN baPWV trend not significant, Martens 2018 NR systolic BP trend not significant in primary analysis, no hard cardiovascular outcome trial in the class, no head-to-head precursor RCT, no trial beyond approximately six months.
7. Major regulatory inflection in 2025 — FDA withdraws 2022 NMN IND exclusion (29 September 2025), TGA permits NMN at 500 mg/day under Determination No. 4 of 2025 (10 December 2025).
8. Brazil remains the strictest jurisdiction — ANVISA RE No. 1,139 of 2022 full-chain prohibition on NMN, no equivalent action elsewhere in the family.

The full 25-year history is more disciplined and more honest than the marketing distillation. Reading the chronology end-to-end is the best inoculation against overclaims in either direction — both the "miracle molecule" framing and the "no evidence" dismissal fail when you actually read what 27 trials, three meta-analyses and four regulatory regimes have established.

Frequently asked questions

Goals this 25-year evidence informs

• Longevity Stack — NAD+ precursor trial history is the spine of the longevity-stack conversation in 2026 — every modern precursor product traces back to the trials catalogued here.
• Cognitive Support — From Birkmayer 2002 jet-lag NADH and Demarin 2004 Alzheimer NADH through Orr 2024 NR in mild cognitive impairment, the cognitive endpoint history is sparse but instructive.
• Heart Health — The McDermott 2024 NICE peripheral artery disease trial is the largest cardiovascular randomized study in the precursor class; Martens 2018 NR healthy-aging blood pressure trend is the longest-cited.

Lifestyles this 25-year evidence informs

• Senior 60+ — The cohort that most modern NAD+ randomized trials enroll — Igarashi 2022, Kim 2022, Morita 2024 NMN; Vreones 2023 NR; Orr 2024 NR-MCI; Demarin 2004 NADH.
• Athletic Performance — Liao 2021 NMN in amateur runners is the single strongest precursor-class athletic-endpoint trial; mechanism context spans NADH redox biology through NMN dose-finding.

Sibling ingredient pages

• NAD+ Cluster Hub
• NMN
• NADH (Reduced NAD)
• NAD+ (Direct Supplementation)

Related Evidence Articles (peer)

• NMN vs NR Decision Tree — downstream precursor choice rooted in the 25-year history reviewed here; cross-read for practical selection.
• Reduced NADH vs NMNH — NAD redox-form comparison adjacent to the precursor chronology; closes the redox-axis evidence loop.

These peer evidence articles cover related NAD-axis mechanisms or downstream precursor choices. Cross-reading builds a holistic NAD evidence picture.

References (30 PubMed-verified citations)

1. Forsyth LM et al. — Therapeutic Effects of Oral NADH in Chronic Fatigue Syndrome (PMID 10071523). Ann Allergy Asthma Immunol 1999.
2. Birkmayer W et al. — Clinical Benefit of NADH in Parkinsonian Patients (PMID 2239495). Advances in Neurology 1990.
3. Nadlinger K, Birkmayer J, Gebauer F — NADH on IL-6 in Human Blood Leukocytes (PMID 11847482). Neuroimmunomodulation 2001.
4. Birkmayer GD, Kay GG, Vurre E — Stabilized NADH Improves Jet-Lag Cognitive Performance (PMID 12385067). Wien Med Wochenschr 2002.
5. Nadlinger K, Westerthaler W, Storga-Tomic D et al. — Extracellular NADH Metabolism Correlates with Intracellular ATP (PMID 12399028). Biochim Biophys Acta 2002.
6. Demarin V et al. — Stabilized Oral NADH in Alzheimer Disease Randomized Trial (PMID 15134388). Drugs Exp Clin Res 2004.
7. Alegre J, Roses JM, Javierre C et al. — NADH in Chronic Fatigue Syndrome Review (PMID 20447621). Rev Clin Esp 2010.
8. Castro-Marrero J, Cordero MD et al. — CoQ10 + NADH in Chronic Fatigue Syndrome (PMID 25386668). Antioxid Redox Signal 2015.
9. Castro-Marrero J, Segundo MJ et al. — Dietary CoQ10 + NADH on Fatigue and Quality of Life (PMID 34444817). Nutrients 2021.
10. Ying W — NAD+/NADH and NADP+/NADPH in Cellular Functions Review (PMID 18020963). Antioxid Redox Signal 2008.
11. Chen AC et al. — Nicotinamide 500 mg BID for Skin Cancer Chemoprevention (ONTRAC) (PMID 26488693). New England Journal of Medicine 2015.
12. Trammell SAJ et al. — Nicotinamide Riboside Is Orally Bioavailable in Mice and Humans (PMID 27721479). Nature Communications 2016.
13. Martens CR et al. — Nicotinamide Riboside in Healthy Middle-Aged and Older Adults (PMID 29599478). Nature Communications 2018.
14. Conze D et al. — NR Safety and Tolerability 8-Week RCT (PMID 31278280). Scientific Reports 2019.
15. Vreones M et al. — NR Lowers Neurodegenerative Biomarkers in Older Adults (PMID 36515353). Aging Cell 2023.
16. Orr ME et al. — NR in Mild Cognitive Impairment RCT (PMID 37994989). GeroScience 2024.
17. McDermott MM et al. — NICE Trial NR in Peripheral Artery Disease (PMID 38871717). Nature Communications 2024.
18. NR-SAFE: High-Dose NR Safety in Parkinson Disease (PMID 38016950). Nature Communications 2023.
19. Irie J et al. — NMN Single-Dose Safety in Japanese Men (PMID 31685720). Endocrine Journal 2020.
20. Yoshino M et al. — NMN Increases Muscle Insulin Sensitivity in Prediabetic Women (PMID 33888596). Science 2021.
21. Liao B et al. — NMN Dose-Finding in 48 Amateur Runners (PMID 34238308). J Int Soc Sports Nutr 2021.
22. Okabe K et al. — 250 mg NMN 12 weeks blood NAD+ doubling (PMID 35479740). Frontiers in Nutrition 2022.
23. Kim M et al. — NMN Afternoon-Dosing Chronobiology RCT (PMID 35215405). Nutrients 2022.
24. Igarashi M et al. — NMN Walking Speed and Grip Strength in Older Japanese Men (PMID 35927255). npj Aging 2022.
25. Fukamizu Y et al. — NMN 1250 mg/day Safety Ceiling RCT (PMID 36002548). Scientific Reports 2022.
26. Yi L et al. — NMN Dose-Finding RCT 300/600/900 mg/day n=80 (PMID 36482258). GeroScience 2023.
27. Pencina KM et al. — MIB-626 NMN 1g BID 14 days NAD+ doubling (PMID 36740954). J Clin Endocrinol Metab 2023.
28. Katayoshi T et al. — NMN baPWV Arterial Stiffness Trend (PMID 36797393). Scientific Reports 2023.
29. Song Q et al. — NMN Anti-Aging Human Trials Update (PMID 37619764). Advances in Nutrition 2023.
30. Zhang J, Poon ET, Wong SH — NMN Meta-Analysis 12 RCTs n=513 (PMID 39116016). Crit Rev Food Sci Nutr 2025.

All identifiers verified via PubMed E-utilities (esearch + esummary) on 26 May 2026. This article does not constitute medical advice and is not a substitute for clinical judgement. Regulatory status varies by jurisdiction; see Regulatory Chronology for FDA, EFSA, ANVISA and TGA positions. The brand mention in ASXAN Evidence Reviews is the publishing entity only; ASXAN does not sell any compound discussed in this chronology.